The incidence of diabetes mellitus and obesity are rapidly rising to epidemic levels in the United States and worldwide. Hyperglycemia, the metabolic hallmark of diabetes is a significant causative factor for the complications of diabetes mellitus, which results in significant morbidity and mortality for millions of Americans. Hyperglycemia is clearly associated with microvascular complications in many organs including the kidney, and diabetic nephropathy is the leading cause of end-stage renal disease (ESRD) in developed countries. In addition, diabetes may lead to macrovascular complications and systemic hypertension. Recent advances on the cellular and kidney-specific effects of hyperglycemia places the activation of the local, intra-renal renin-angiotensin system (RAS) as a strong candidate for the core abnormality that leads to other biochemical and cellular defects and the resulting renal tissue injury. Renin release from juxtaglomerular cells is the rate-limiting step of RAS activation. Novel discovery of the G-protein-coupled receptor GPR91, activated by citric acid cycle intermediate succinate, may provide a link between glucose metabolism and renin-dependent increases in blood pressure. We have recently established an imaging technique in which renin content, release, and tissue activity can be directly visualized in the intact living kidney tissue. The broad, long-term objective of this application is to establish that hyperglycemia in early diabetes causes the activation of the newly identified, kidney-specific metabolic receptor GPR91 which in turn initiates paracrine signaling and triggers renin release and glomerular hyperfiltration. Specific aims of this grant are to identify the cell types and molecules involved in succinate signaling, establish the mechanism of high glucose-induced renin release in vitro, and test the importance of GPR91/renin in the development of diabetic complications in vivo. Primary cell cultures, the isolated, in vitro microperfused afferent arteriole-glomerulus preparation, and in vivo mouse and rat kidney animal models will be used in combination with multi-photon fluorescence microscopy, and real-time imaging. These studies should yield clinically important information that can be used to develop new drugs and therapeutic approaches for the better treatment of diabetic complications in the kidney as well as high blood pressure.